SYNTHESIS OF SUBSTITUTED NAPHTHALENES THROUGH FUNCTIONALISED ORGANOLITHIUM COMPOUNDS

Miguel Yus, Benjamín Moreno, Francisco Foubelo* and Abdeslam Abou

Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain.

Abstract: Reaction of the dinaphthooxepin 5 with a stoichiometric amount of lithium naphthalenide in THF at –78ºC for 1 h yielded exclusively the dianionic species 10, which by reaction with water at the same temperature gave the hydroxybinaphthyl derivative 11 in 81% yield. Treatment of the benzoisochroman 12 with an excess of lithium and a catalytic amount of DTBB (5 mol%) at –50ºC for 5 h followed by reaction with different electrophiles {H₂O, D₂O, Bu^tCHO, PhCHO, Me₂CO, Et₂CO, [CH₃(CH₂)₄]₂CO, (CH₂)₅CO, (CH₂)₇CO} at –78ºC led, after hydrolysis with water, to alcohols 15. When alcohoxide 14, which is formed after addition of the first electrophile [Bu^tCHO, (CH₂)₂CO] is stirred at room temperature for 1 h, a new lithiation occurred and after addition of a second electrophile [Bu^tCHO, (CH₂)₂CO, CO₂] and final hydrolysis, 1,8-difunctionalised naphthalenes 17 are formed.   

Keywords: catalysed lithiation, reductive opening, functionalised naphthalenes, organolithium compounds.

INTRODUCTION

Functionalised organolithium compounds¹ are of interest in synthetic organic chemistry because by reaction with electrophilic reagents polyfunctionalised molecules are obtained in only one step.² These compounds can be prepared following different strategies, the reductive opening of appropriate oxygen-, nitrogen- and sulfur-containing heterocycles³ by means of lithium metal being the most elegant and direct one. Among the appropriate heterocycles for undergoing the reductive opening are the heterocycles with activated bonds, as in the case of compounds with allylic⁴ and benzylic⁵ carbon-heteroatom bonds as well as cyclic aryl ethers⁶ and thioethers.⁷ These processes have to be performed under very mild reaction conditions in order to avoid the decomposition of the resulting highly reactive functionalised organolithium compound, and because of that, in the last few years a methodology consisting in the use of an excess of lithium in the presence of a catalytic amount of an arene has been developed as a potent lithiating agent,⁸ naphthalene and 4,4’-di-tert-butylbiphenyl (DTBB) being the most commonly used.⁹ On the other hand, there are many biologically active natural products with a naphthalene core, naphthalene derivatives being of great interest, especially those containing a 1,1’-binaphthyl moiety, because they have played a central role as chiral ligands in the development of enantioselective catalysis and also as molecular hosts for the complexation of organic guest molecules.¹⁰ Considering these antecedents we decided to study the reductive opening of different naphthyl and 1,1’-binaphthyl oxygen- and sulfur-containing heterocycles and the synthetic applications of the resulting functionalised organolithium compounds when reacting with electrophiles.

RESULTS AND DISCUSSION

Dinaphthothiepin 4 and dinaphthooxepin 5 were prepared from commercially available 1-bromo-2-methylnaphthalene 1 as it is described in Scheme 1.¹¹

Scheme 1. Reagents and conditions: i) Mg, Et₂O-PhH (1/1), 20ºC, 5 h; ii) 1 (1 eq.), (Ph₃P)₂NiCl₂, 40ºC, 15 h; iii) NBS (2.5 eq.), AIBN cat., CCl₄, 80ºC, 4 h; iv) Na₂S·9H₂O, DMF, 100ºC, 1 h; v) KOH 15 M, 1,4-dioxane, 100ºC, 16 h.

The reaction of the dinaphthothiepin 4 with an excess of lithium in the presence of a catalytic amount of DTBB (5 mol%) in THF at –78ºC for 30 min followed by reaction with acetone as electrophile at the same temperature gave, after acidic hydrolysis, an almost 1:1 mixture of the sulfanyl alcohol 8 and the diol 9 in 68% yield (Scheme 2). Under these reaction conditions, reductive opening of the dinaphthothiepin 4 takes place to give first organolithium intermediate 6, which partially undergoes a new lithiation through a benzylic carbon-sulfur bond cleavage (due to the presence of excess of lithium in the reaction medium) to give the dilithium derivative 7. Very similar results were obtained from compound 5 under the same reaction conditions.

Scheme 2. Reagents and conditions: i) Li, DTBB (5% molar), THF, -78ºC, 30 min; ii) Me₂CO,

-78ºC; iii) 3 M HCl, -78 → 20ºC.

However, the reaction of the dinaphthooxepin 5 with a stoichiometric amount of lithium naphthalenide in THF at –78ºC for 1 h yielded exclusively the dianionic species 10, which by reaction with water at the same temperature gave the alcohol 11 in 81% yield, so selective reductive opening being possible to be achieved under these reaction conditions (Scheme 3). The reaction of intermediate 10 with different electrophiles would give functionalised alcohols. All these compounds could be prepared in enantiomerically pure form by using either (R)- or (S)-2,2’-bis(bromomethyl)-1,1’-binaphthyl (3).¹²

Scheme 3. Reagents and conditions: i) LiC₁₀H₈, THF, -78ºC, 1 h; ii) H₂O, -78 → 20ºC.

Finally, we studied also the lithiation of the benzoisochroman derivative 12, a naphthalene oxygen-containing heterocycle derivative, which can be prepared from commercially available 1,8-naphthalic anhydride.¹³ Azzena et al. studied the lithiation of 12 using an excess of lithium (5 equiv) and a catalytic amount of naphthalene (10 mol%) at different temperatures and reaction times. They got always after hydrolysis with water the expected alcohol 15 (E₁ = H) in moderate yields (less than 55%) and variable amounts of 1,8-dimethylnaphthalene (17, E₁ = E₂ = H). The late compound comes from a double reductive cleavage reaction. A better selectivity was obtained when the process was performed with potassium metal instead of lithium.¹³ In our case, the reaction of the benzoisochroman 12 with an excess of lithium in the presence of a catalytic amount of DTBB (5 mol%) in THF at –50ºC for 5 h gave the organolithium intermediate 13, which reacted with different electrophilic reagents at the same temperature yielding compounds 14, which after hydrolysis with water gave the expected alcohols 15 (Scheme 4, Table 1, entries 1-9). It was possible to introduce two different electrophilic fragments at both benzylic positions in a sequential manner when alcoholate 14  was stirred at 0ºC for 1 h, so a second lithiation took place due to the excess of lithium still present in the reaction medium, giving a new organolithium compound 16, which reacted with a second electrophile (E₂) at low temperature giving, after hydrolysis with water, difunctionalised compounds 17 (Scheme 4, Table 1, entries 10-14).

Scheme 4. Reagents and conditions: i) Li, DTBB (5% molar), THF, -50ºC, 6 h; ii) E₁⁺ = H₂O, D₂O, Bu^tCHO, PhCHO, Me₂CO, Et₂CO, [CH₃(CH₂)₄]₂CO, (CH₂)₅CO, (CH₂)₇CO, -78ºC; iii) H₂O, -78 → 0ºC; iv) 0ºC, 1 h; v) E₂⁺ = H₂O, Bu^tCHO, CO₂, -78ºC, 15 min; vi) H₂O, -78 → 20ºC, followed by 3 M HCl in the case of E₂⁺ = CO₂.

Table 1. Preparation of compounds 15 and 17

^a All products were > 95% pure (GLC and 300 MHz ¹H NMR) and were fully characterised by spectroscopic means.

^b Isolated yield after column chromatography.

CONCLUSIONS

From the results described here, we conclude that functionalised binaphthyls 8, 9 and 11 as well as difunctionalised naphthalenes 15 and 17 can be accessible from the dinaphthotiepin 4, the dinaphthooxepin 5 and the benzoisochroman 12 through a tandem lithiation-reaction with electrophiles or a double sequential lithiation-reaction with electrophiles in the case of compounds 17.

Acknowledgements: Financial support from the DGES (Spanish Ministerio de Educación y Cultura, project no. PB-97-0133) and from the Generalitat Valenciana (projects no. GV01-443 and CTIDIB/2002/318) is gratefully acknowledged.

REFERENCES AND NOTES

1.      For reviews, see: (a) Nájera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155. (b) Nájera, C.; Yus, M. Recent Res. Dev. Org. Chem. 1997, 1, 67. (c) Nájera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867.

2.      Wakefield, B. Organolithium Methods, Academic Press, London, 1988.

3.      For a review, see: (a) Yus, M.; Foubelo, F. Rev. Heteroatom Chem. 1997, 17, 73. (b) Yus, M.; Foubelo, F. Targets in Heterocyclic Systems 2002, 6, 136.

4.      (a) Sabes, S. F.; Urbanek, R. A.; Forsyth, C. J. J. Am. Chem. Soc. 1998, 120, 2534. (b) Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1998, 39, 3303. (c) Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron 2000, 56, 1745. (d) Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron Lett. 2000, 41, 1661.

5.      (a) Azzena, U.; Demartis, S.; Fiori, M. G.; Melloni, G.; Pisano, L. Tetrahedron Lett. 1995, 36, 5641. (b) For a review, see: Azzena, U. Trends Org. Chem. 1997, 6, 55. (c) Azzena, U.; Carta, S.; Melloni, G.; Sechi, A. Tetrahedron 1997, 53, 16205.

6.      (a) Maercker, A. Angew. Chem. Int. Ed. Engl. 1987, 26, 972. (b) Lazana, M. C. R. L. R.; Franco, M. L. T. M. B.; Herold, B. J. J. Am. Chem. Soc. 1989, 111, 8640. (c) Casado, F.; Pisano, L.; Farriol, M.; Gallardo, I.; Marquet, J.; Melloni, G. J. Org. Chem. 2000, 65, 322. (d) Azzena, U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org. Chem. 1990, 55, 5386. (e) Azzena, U.; Denurra, T.; Melloni, G.; Fenude, E.; Rassu, G. J. Org. Chem. 1992, 57, 1444.

7.      (a) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978, 43, 1064. (b) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1979, 44, 713. (c) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.

8.      For the first account on this reaction, see: Yus, M.; Ramón, D. J. J. Chem. Soc., Chem. Commun. 1991, 398.

9.      For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 155. (b) Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225. (c) Yus, M. Synlett 2001, 1197.

10.    de Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L. Tetrahedron 2003, 59, 7.

11.        Maigrot, N.; Mazaleyrat, J.-P. Synthesis 1985, 317.

12.    (a) Gingras, M.; Dubois, F. Tetrahedron Lett. 1999, 40, 1309. (b) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679.

13.    Azzena, U.; Demartis, S.; Pilo, L.; Piras, E. Tetrahedron 2000, 56, 8375.